Research
Down Syndrome Research
Down syndrome is not a disease; therefore, our lab is not focused on “curing” Down syndrome. Instead, we aim to improve quality of life by addressing common phenotypes and co-occurring conditions in people with Down syndrome, including developmental delays, autoimmune conditions, leukemia, cardiovascular abnormalities, Alzheimer’s disease and more.
Our research aims to understand the gene networks altered by the presence of an extra copy of chromosome 21 (called trisomy 21), decipher their impacts on biology, and identify safe therapeutic options. These efforts coalesce in the Crnic Institute Human Trisome Project®, a biobank paired with multi-omics analyses aimed at understanding why individuals with Down syndrome are more susceptible to certain conditions, such as Alzheimer’s disease, while they are protected from others, including many solid tissue-derived cancers. Our ultimate goal is to advance a personalized medicine approach to Down syndrome while also creating therapeutic leverage - enabling discoveries for millions of others who are affected by any one of the many medical conditions modulated by trisomy 21.
Human Trisome Project data is open to the public through the online research portal called the TrisomExplorer.
One of the most important studies we are performing in this context is a clinical trial entitled "Safety and efficacy of tofacitinib for immune skin conditions in Down syndrome." With this study, we are taking a discovery made by the Human Trisome Project – that trisomy 21 causes hypersensitive interferon signaling, leading to immune dysregulation – and testing a JAK inhibitor to mitigate the interferon response and resulting phenotypes – in this case, a collection of skin conditions driven by immune dysregulation that are more common in individuals with Down syndrome. We are also beginning to assess whether JAK inhibitors could improve other common conditions in Down syndrome, such as hypothyroidism and cognitive impairment.
Dr. Espinosa is Executive Director of the Linda Crnic Institute for Down Syndrome, co-leader of the INCLUDE DCC and the Espinosa Lab partners closely with Crnic Institute Members to advance research in Down syndrome.
Featured Publications
1. Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.
2. Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome
Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.
3. Multidimensional definition of the interferonopathy of Down syndrome and its response to JAK inhibition
Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.
4. Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model
Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.